Inflammation is a natural reaction of living organisms to external factors, such as infection, trauma, etc., which damage their tissues and cells, and varies types of cells, mediums, and stimulators are involved. Acute inflammation is a short-term reaction, which will generally promote the organism to heal. On the contrary, chronic inflammation is an adverse reaction with protracted disfunction. In fact, chronic inflammation involves many systemic and local pathological states and pathogenesis of the living organisms, wherein the former is, such as brain nerve disfunction, diabetes, hepatitis, rheumatoid arthritis and tumors in different part of the body, and the latter is, such as uveitis, keratitis etc.
Epidemiological investigation showed that the incidence and morbidity of uveitis, as one of the major blinding diseases, is increased. In US and Europe, uveitis accounts for about 5-20% of blinding diseases, while the number goes up to about 25% in developing countries. Uveitis has caught the attention from ophthalmology field in the world since it mainly affect the young adults, is hard to treat and prone to recur, and may cause blind if not being timely or proper treated.
Autoimmune disease and infection are the main pathogenic factors for uveitis. When the organism is infected, the macrophages in the body are activated by bacterial toxin (eg. lipopolysaccharide), thereby inducing the secretion of a series of inflammation-related cytokines and chemokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, (MCP)-1, etc., and these inflammatory factors are essential to many chronic inflammatory diseases.
For a long time, corticosteroid hormones have been the best choice for treating uveitis. Especially for treating obstinate uveitis, long-term medication is needed for preventing its recurrence. However, there are many potential side effects for corticosteroid hormone, such as intraocular hypertension, cataract, infection, delayed wound healing, etc., thus limiting the clinical application of the medicine. Immunosuppressors, such as cyclosporine A, FK506, etc., are the second-line medicine for inhibiting inflammation, and also have severe side effects such as liver and kidney injury. At present, some therapeutic effects have been achieved by using biological agents such as monoclonal antibodies (eg. anti-TNF agents and IL receptor antagonist, lymphocytes activation inhibiting agents, immunoregulating and anti inflammatory cytokines agents, etc.) to inhibit or block disease-related lymphocytes, cytokines or cytokine receptors. However, the biological agents belong to macromolecule proteins, therefore they are hard to synthesize and too expensive to be clinically promoted. Besides, the specificity of ocular agents should be sufficiently considered in developing effective anti-inflammation agents.
Firstly, many effective macromolecule antagonists are weaken or failed to reach intraocular focus due to the existence of several anatomic and physiological barriers in the eye balls. In the case of commonly used ocular surface administration route, the agents have to successively penetrate the lipophilic tight junctions between corneal epithelial cells and then the hydrophilic corneal stroma. Thus, only the agents with appropriate lipophilicity, low molecular weight or the capability of binding with the transporters in ocular surface tissues can reach the anterior chamber and function effectively. The agent concentration reached in the eyes will be greatly reduced due to the blood-aqueous barrier in iris and blood-retina barrier in retina-choroid if the agents are administered orally.
Secondly, the solubility of the drugs in the hydrophilic tears, aqueous humor, and vitreous humor is positively correlated to their effectiveness.
Finally, the bioavailability of ocular agents is very low. The administration concentration must be increased to improve the bioavailability.
Therefore, there is an urgent need to develop a small molecule anti-inflammation agent which is suitable for eye ball tissues, safe and effective.